PMID- 11342575
OWN - NLM
STAT- MEDLINE
DCOM- 20010607
LR  - 20181113
IS  - 0021-9738 (Print)
IS  - 0021-9738 (Linking)
VI  - 107
IP  - 9
DP  - 2001 May
TI  - Tissue factor pathway inhibitor-2 is a novel inhibitor of matrix 
      metalloproteinases with implications for atherosclerosis.
PG  - 1117-26
AB  - Degradation of ECM, particularly interstitial collagen, promotes plaque 
      instability, rendering atheroma prone to rupture. Previous studies implicated 
      matrix metalloproteinases (MMPs) in these processes, suggesting that dysregulated 
      MMP activity, probably due to imbalance with endogenous inhibitors, promotes 
      complications of atherosclerosis. We report here that the serine proteinase 
      inhibitor tissue factor pathway inhibitor-2 (TFPI-2) can function as an MMP 
      inhibitor. TFPI-2 diminished the ability of the interstitial collagenases MMP-1 
      and MMP-13 to degrade triple-helical collagen, the primary load-bearing molecule 
      of the ECM within human atheroma. In addition, TFPI-2 also reduced the activity 
      of the gelatinases MMP-2 and MMP-9. In contrast to the "classical" tissue 
      inhibitors of MMPs (TIMPs), TFPI-2 expression in situ correlated inversely with 
      MMP levels in human atheroma. TFPI-2 colocalized primarily with smooth muscle 
      cells in the normal media as well as the plaque's fibrous cap. Conversely, the 
      macrophage-enriched shoulder region, the prototypical site of matrix degradation 
      and plaque rupture, stained only weakly for TFPI-2 but intensely for gelatinases 
      and interstitial collagenases. Evidently, human mononuclear phagocytes, an 
      abundant source of MMPs within human atheroma, lost their ability to express this 
      inhibitor during differentiation in vitro. These findings establish a new, 
      anti-inflammatory function of TFPI-2 of potential pathophysiological significance 
      for human diseases, including atherosclerosis.
FAU - Herman, M P
AU  - Herman MP
AD  - Leducq Center for Cardiovascular Research, Division of Cardiovascular Medicine, 
      Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, 
      Boston, Massachusetts 02115, USA.
FAU - Sukhova, G K
AU  - Sukhova GK
FAU - Kisiel, W
AU  - Kisiel W
FAU - Foster, D
AU  - Foster D
FAU - Kehry, M R
AU  - Kehry MR
FAU - Libby, P
AU  - Libby P
FAU - Schonbeck, U
AU  - Schonbeck U
LA  - eng
GR  - P50 HL056985/HL/NHLBI NIH HHS/United States
GR  - HL-56985/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - J Clin Invest
JT  - The Journal of clinical investigation
JID - 7802877
RN  - 0 (Glycoproteins)
RN  - 0 (Matrix Metalloproteinase Inhibitors)
RN  - 0 (Procollagen)
RN  - 0 (Recombinant Proteins)
RN  - 0 (Serpins)
RN  - 0 (tissue-factor-pathway inhibitor 2)
SB  - IM
MH  - Aorta/pathology
MH  - Arteriosclerosis/*etiology
MH  - Carotid Arteries/pathology
MH  - Dose-Response Relationship, Drug
MH  - Glycoproteins/genetics/*pharmacology
MH  - Humans
MH  - Macrophages/metabolism
MH  - *Matrix Metalloproteinase Inhibitors
MH  - Muscle, Smooth, Vascular/metabolism
MH  - Procollagen/metabolism
MH  - Protein Binding
MH  - Protein Processing, Post-Translational/drug effects
MH  - Recombinant Proteins/pharmacology
MH  - Serpins/*pharmacology
PMC - PMC209273
EDAT- 2001/05/09 10:00
MHDA- 2001/06/08 10:01
PMCR- 2001/05/01
CRDT- 2001/05/09 10:00
PHST- 2001/05/09 10:00 [pubmed]
PHST- 2001/06/08 10:01 [medline]
PHST- 2001/05/09 10:00 [entrez]
PHST- 2001/05/01 00:00 [pmc-release]
AID - 10403 [pii]
AID - 10.1172/JCI10403 [doi]
PST - ppublish
SO  - J Clin Invest. 2001 May;107(9):1117-26. doi: 10.1172/JCI10403.